Mini ReviewCaloric restriction in humans
Introduction
Since the initial report by McCay et al. (1935) that caloric restriction (CR) increases maximal longevity in rats, there have been hundreds of studies showing that CR slows aging in yeast, flies, worms, fish, mice and rats. The studies on mice and rats have demonstrated that CR (defined as calorie restriction without malnutrition) slows primary aging, has a protective effect against secondary aging, and markedly decreases the incidence of malignancies (Weindruch and Sohal, 1997). As used here, secondary aging is defined as the deterioration in tissue structure and biological function that is secondary to disease processes and harmful environmental factors. Protection against secondary aging results in rectangularization of the survival curve with an increase in average longevity but no increase in maximal longevity. Primary aging is the inevitable, progressive decline in tissue structure and biological function that occurs with advancing age, independently of disease or harmful lifestyle and environmental factors. Slowing of primary aging results in an increase in maximal longevity. While the demarcation between primary and secondary aging can become somewhat blurred, an understanding of the difference between these processes is essential for interpreting the results of studies of the effects of an intervention on longevity. CR is the only intervention that has consistently been shown to slow primary aging, as evidenced by an increase in maximal longevity, i.e. the finding that the oldest CR rats and mice survive ∼20–50% longer than the oldest ad libitum fed controls (Weindruch and Walford, 1988).
The large expenditure of research funds, resources and time on studies of the effects of CR in yeast, worms, flies, and rodents over the past 50+ years was, no doubt, largely motivated by the possibility that information obtained on these species has relevance to humans. However, while findings on rats, mice and perhaps also yeast, worms, and flies, can suggest possible mechanisms that are relevant to humans, the only way to determine whether CR “works” in humans is to conduct studies on people. Such studies are difficult to perform in free-living people and there is, therefore, little information available on the effects of CR, particularly long-term CR, in humans. This situation is starting to change and, while research on CR in humans is still at an early stage, a modest amount of information has accumulated.
Section snippets
Okinawan centenarians
Severe, long-term CR has been a fact-of-life for many human populations throughout history, and is still prevalent among the poor in third world countries. However, these natural experiments have generally not provided information regarding the effect of CR on health and longevity, because low calorie diets necessitated by poverty are frequently deficient in essential nutrients and because of the high prevalence of acute and chronic infectious diseases in these populations. An exception to this
Studies on Rhesus monkeys
It seems unlikely that it will ever be established with certainty whether CR increases maximal lifespan in humans. However, there are two studies of CR in Rhesus monkeys in progress, one at the University of Wisconsin at Madison, the other at the National Institute on Aging’s, Gerontology Research Center, that should within the next 15–20 years determine whether CR increases maximal longevity in non-human primates. These studies have already shown that CR protects against development of insulin
Studies in humans
Because it is not feasible to conduct studies of the effect of CR on longevity in humans, surrogate measures have to be used. One approach is to determine whether humans undergo the same biological adaptations to CR that occur, and may be involved in slowing primary aging, in rodents. Another is to determine the effects of CR on risk factors for secondary aging. A third approach is to measure physiological variables that deteriorate progressively with aging, i.e. biomarkers of aging.
CR in biosphere 2
Biosphere 2 is an enclosed ∼3 acre space which was designed to be an “ecological mini-world”. Eight volunteers were sealed inside Biosphere 2 for two years. During much of this period, food availability was severely limited because the amount of food they were able to grow was less than planned. The BMI of the 4 men decreased 19% to 19.3 ± 0.9 kg/m and the BMI of the 4 women decreased 13% to 18.5 ± 1.2 kg/m. Changes that occurred in response to this food shortage included marked reductions in blood
CALERIE Phase 1
CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Calorie Intake) is a research program that involves three research centers (Tufts University, Pennington Biomedical Research Center, and Washington University) and a coordinating center (Duke University) that was initiated by the National Institute on Aging (NIA), and is supported by NIH Cooperative Agreement AG20487 from the NIA, to obtain information on the effects of sustained CR in humans. The Phase 1 of CALERIE consisted of
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